ABSTRACT Given the growing prevalence of autism spectrum disorder (ASD), there is an urgent need to better understand its etiology. Genetic variation identified through association and sequencing studies has provided valuable clues about the biological underpinnings of ASD, which is highly heritable. Our objective is to combine family-based genetic studies of ASD currently ongoing at the Autism Spectrum Program of Excellence at the University of Pennsylvania (Penn ASPE) with the Simons Simplex Collection (SSC) and SPARK genetic data to investigate fundamental mechanisms contributing to ASD risk, specifically in ASD subjects without intellectual disability (ASD w/o ID) and their families. New datasets, such as SSC, SRARK and our own ASPE collection, will allow us to genetically dissect polygenic risk burden and address a longstanding but unexplored hypothesis that assortative mating may contribute to ASD liability. If assortative mating is present, this affects a broad range of studies of genetics of ASD and will be important to consider in re-analysis of existing data and design of future studies. Having scientific evidence to support or refute these theories may be of immediate and direct value to the ASD community. We propose the following Specific Aims: Aim 1) To genetically dissect genomic features that differentiate ASD with and without ID. Genetic dissection of polygenic risk scores and rare or low frequency variants known to be associated with ASD will be further combined with the analysis of ancestry and trait-related assortative mating across a large number of ASD families (Aim 2). Aim 2) To characterize assortative mating in parents of probands with ASD. We hypothesize that assortative mating, at a trait-level and a genomic level, will be more prevalent in parents of ASD w/o ID probands. Correlation of the PRS and the degree of assortative mating in families with a rich collection of phenotypes and traits (in SPARK, SSC and ASPE) will reveal important insights into polygenic architecture and may provide critical mechanistic threads. The focus of this proposal on ASD w/o ID is novel because most previous ASD genetics findings have been in studies that recruited ASD probands with ID. Similarly, the role of ancestry and trait- based assortative mating in ASD families may reveal unique aspects of genetic architecture in some ASD families and thereby facilitate interpretation genetic findings. As most standard genetic analysis approaches assume random mating, if assortative mating on the basis of social responsiveness or other ASD-related traits is present, this has implications for a wide range of studies of ASD genetics.